Topoisomerase IIβ Mediates Doxorubicin-Induced Cardiotoxicity

Abstract

Deletion of Top2b in cardiomyocytes protects mice from cardiotoxicity caused by doxorubicin.

Major finding: Deletion of Top2b in cardiomyocytes protects mice from cardiotoxicity caused by doxorubicin.

Concept: Doxorubicin and TOP2β induce DSBs and transcriptional changes that result in mitochondrial dysfunction.

Impact:TOP2B may be useful as a predictor of susceptibility to doxorubicin-induced cardiotoxicity.

Doxorubicin is a widely used chemotherapeutic agent, but its clinical use is often limited by dose-dependent cardiotoxicity. Doxorubicin induces double-strand breaks (DSB) and cell death by intercalating into DNA and blocking the activity of the topoisomerase II (TOP2) enzymes, TOP2α and TOP2β. TOP2α is highly expressed in tumors compared with quiescent tissues and is thus thought to mediate doxorubicin's cytotoxic effects on cancer cells. Zhang and colleagues hypothesized that doxorubicin-induced cardiotoxicity might be mediated by TOP2β, the only TOP2 enzyme expressed in cardiomyocytes. To evaluate the role of TOP2β in doxorubicin-induced cardiac dysfunction, the authors generated conditional mice with cardiomyocyte-specific deletion of Top2b and treated them with doxorubicin. After 16 hours of treatment, wild-type cardiomyocytes showed marked upregulation of apoptotic genes and activation of the DNA damage response compared with Top2b-null cardiomyocytes, consistent with a role for TOP2β in doxorubicin-induced DSBs and cell death. After 72 hours of exposure to doxorubicin, genes required for mitochondrial biogenesis and oxidative phosphorylation were selectively repressed in wild-type cardiomyocytes, suggesting a mechanism by which doxorubicin might exert negative effects on mitochondria in the presence of TOP2β. Indeed, mitochondrial membrane potential and oxygen consumption were compromised, and structural damage and reactive oxygen species generation were increased in wild-type cardiomyocytes compared with their Top2b-null counterparts. Chronic doxorubicin exposure also increased end systolic and end diastolic volumes and reduced ejection fraction in wild-type mice but not Top2b-null mice, further indicating that the harmful effects of doxorubicin on cardiac function require TOP2β. These findings suggest that high expression of TOP2β in cardiomyocytes may be a predictive biomarker for doxorubicin-induced cardiotoxicity and that anticancer agents that selectively target TOP2α may be less cardiotoxic.